Focus: Importance of the Dopaminergic system in relation to Neuroscience, Neurology, and Psychiatry

By Group D: Vielka Inoa, Angelia Ozuna, Sky Johnson, Alia Abdelaziz

1. Introduction 

Further Advancements in Dopamine research are key to biological psychiatry, psychopharmacology, as well as treatments for chronic neurological illnesses and their imperative differences caused by age, gender and ethnicity. Dopamine is a neurotransmitter that is produced in the substantia nigra, ventral tegmental area, and hypothalamus of the brain, the dysfunction of the dopamine system has been implicated in different nervous system diseases such as alzhimers, parkinsons, attention deficit hyperactivity disorder (ADHD), etc. A review taking into account all those diseases is the scope of the present review, which will focus on the main dopamine-associated diseases, namely, Parkinson’s disease, ADHD and trauma. The study of dopamine and causality relationships with psychological factors and external factors such as diet and drug use, makes for a crucial focal point in the search for chronic neurological illnesses specifically in minorities and younger generations. Those suffering from Parkinson’s and ADHD  suffer from low brain dopamine concentrations, affecting their motivation, memory and cognitive control. Studies show Dopamine reuptake inhibitors extend the stay of dopamine in the synaptic cleft, potentially being able to identify a way to increase dopamine after great loss of the neurotransmitters. Though further research must be done to develop accurate dopamine quantification mechanisms and methods for the dopamine channel deficiencies to be visualized in diseased brains. 

2. Methodology: 

   Examination of dopamine has been trialed in many ways, from a laboratory approach to measurement and analysis. To in patient translational methods allowing us to see the connection between dopamine levels and the brain’s processes, from attention deficits to trauma and psychosis. 

    In Neuroscience examination of boutons at synapses allows relative assessment of dopamine signaling. However, despite how much information is known about dopamine, identification of the most reliable method for quantifying dopamine boutons has yet to be established. To answer this question, we examined dopamine boutons in the prefrontal cortex of P42 mice brains using two different methods. First, we used a mouse line that expresses a fluorescent dopaminergic reporter, DAT-Ai14, to assess levels of dopaminergic signaling using a transgenic approach to label boutons. Next, we used a dopamine specific antibody, Anti-TH, to assess levels of dopaminergic signaling using a histological approach to label boutons. This lights up the dopamine receptor cells across different areas of the brain. Then, we manually quantified boutons across the entire prefrontal cortex to compare differences in relative levels of dopaminergic signaling. 

Further examinations can be made with targeted approaches like in Dr.Wei-Dong Yao’s work , examining specific dopamine interacting proteins or DNA and their effects on dopamine and other biochemical levels. DA receptors interact and co-localize with a number of PSD proteins in dendritic spines. 

This can then be applied to real life patients where said reactions can be analyzed and connected to psychosis, childhood trauma etc. In one study conducted by Dr. Tarik Dahoun, looking at dopaminergic effects on psychiatric patients, participants attended a screening visit to check eligibility criteria, and underwent two (PHNO) PET scans on separate days: the first following a single oral dose of placebo, and the second following a single oral dose of dexamphetamine ( a dopamine mimicking stimulant) (500 µg/kg) in a fixed order. On the first scan day, participants completed the Childhood Trauma Questionnaire (CTQ). On both scan days, positive (psychotic) symptoms, negative symptoms and general psychopathology symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS) at baseline (pre-dosing with placebo or dexamphetamine), 60 min post-dosing, 120 min post-dosing, and after the scan (275 min post-dosing). Participants were blind to placebo/dexamphetamine administration. The rater was blind to childhood trauma load and dexamphetamine-induced dopamine release. All participants provided urine samples prior to each scan to screen for current recreational drug use. Participants were asked to abstain from smoking, drinking coffee, eating and using alcohol overnight (minimum 10 h) prior to their PET scans. In order to examine whether the relationship between childhood trauma and positive psychotic symptoms is mediated by dopamine release, we performed a mediation analysis with childhood trauma as the independent variable, dexamphetamine-induced dopamine release as the mediator variable, and dexamphetamine-induced positive symptoms as the dependent variable, using the ‘Model 4’ template implemented in the PROCESS. Effect sizes were estimated using 5000 bias corrected bootstrap samples. Mediation was deemed to be significant if 0 was not contained within the 95% bootstrap confidence intervals of the indirect effect, testing the combined effects of paths a (CTQ to dexamphetamine-induced dopamine release) and b (dexamphetamine-induced dopamine release to dexamphetamine-induced positive psychotic symptoms). These processes can be used to assess long term effects of trauma on the brain along with similar diseases with a physical-neurochemical relationship. From ADHD to Parkinsons. 

3. Data Overview and Models

Dopamine is vital for many physiological functions including mood, movement, reward, and cognitive control. Researching its system is important due to its correlation with various disorders, neurological/ psychological fields and its varying external factors. Prefrontal dopamine projections can be labeled with multiple methods but the relative strength and weakness of labeling methods have yet to be established. This data will provide further insight into an optimal method for quantifying dopamine innervation, which will improve our understanding of the neurological and neuropsychiatric disorders that result from impaired dopaminergic signaling. 

Fig. 1: Prominent variation of Bouton Labeling methods

Figure 1 demonstrates the prominent variations in bouton labeling methods. For example, TH-Immunohistological/ antibody stain and Transgenic DAT- Ai14 reporter. The chart displays a clear reading of the TH-antibody stain highlighting more boutons than the Transgenic DAT- Ai14 reporter. This demonstrates a progression in the finding of a strong dopamine labeling method. The TH-immunostaining method consistently shows to label more than the DAT reporter. 

Considering the dopaminergic system displays a direct effect on psychological function through many genders, ages, and specifically ethnicities, utilizing the most accurate method in labeling would benefit the psychological advancements. 

Fig. 2: Most Prominent Differences between African-American and white respondents in perceptions and attitudes towards ADHD

Figure 2 shows how diagnosis and treatment of ADHD within African Americans greatly differs compared to people of White ethnicity as well as the difference between the beliefs of diagnosis of ADHD. African Amercians are shown to have a lower familiarity with ADHD itself yet consider ADHD to be a “very serious” condition. Additionally, African Americans are more likely than other ethnic groups to be diagnosed with ADHD.

The importance of being able to utilize proper methods is key in advancing the ability of gaining a proper diagnosis for neurological and/ or psychological disorders.

IV Discussion

       Due to the fact that the dopaminergic system plays a vital role in many of the physiological functions of a person, it is important to maintain a healthy dopamine level. Deficiencies or injury to the dopaminergic system can cause a series of side effects.

          Motivated behavior is under the control of the mesofrontal dopaminergic circuit. This circuit links the midbrain motivation region to the cortical executive center. As a result deprivation in this dopaminergic system can lead to significant problems. Such problems include “deficiencies in this circuit are associated with adolescent-onset psychiatric disorders in humans” (Surjeet Mastwal et Al. 2014). Dopamine levels are linked to a number of neurological and mental health conditions. Some dopaminergic transmission dysfunctions include, “neurological and neuropsychiatric disorders, including Parkinson’s disease, Huntington’s diseases, schizophrenia, attention-deficit hyperactivity disorder (ADHD), and drug addiction [1–2]. Drugs targeting dopaminergic mechanisms are widely used to manage these and other conditions.” (Wei-Dong Yao et al. 2009). Increased and decreased levels of dopamine in certain areas of the brain can be linked to support impulse control, addiction and gambling. Low amounts of dopamine are linked to depression, decreasing motivation, restless syndrome, shaking hands and other tremors as well.

          Researching the dopaminergic system is particularly important due to its causal relationship with various disorders, Along with its foundational connection to big pharma in both the neurological and psychological fields. Dopamine signaling’s ability to vary given external factors also makes it a crucial focal point in the search for chronic neurological illness in minorities and younger populations.

         It had been determined that, “ADHD appears to be similar in African Americans and white populations. However, fewer African-American than white children are diagnosed and treated for ADHD.” (Bailey and Owens 2005). This could be for a multitude of reasons. According to the data shown previously the statistics showed that 

-Limited access to healthcare professionals knowledgeable about ADHD prevents children from receiving appropriate treatment African American 44%, white 39%. 

-African Americans are more likely than other ethnic groups to be diagnosed with ADHD African American 41%, white 13%. 

-Aware of treatments that help to lessen the symptoms of ADHD African American, 66%   white, 84%

         Further research on the dopaminergic  system could help to determine exactly why certain communities might be affected more, less or the same and what factors play into races having a higher attention-deficiency or hyperactivity disorder. 

       The “Diagnosis of a primary neurotransmitter disorder will, for the majority of patients, have important therapeutic implications. This concept has again been very recently and beautifully – exemplified by the report of patients with mutations in VMAT2 with clinical symptoms of dopami-nergic deficiency, and their remarkable clinical response to dopamine agonists.” (Kurian n.d). By determining the role dopamine plays in childhood disorders through further research, there could then be treatments that can be administered in order to correct or diminish the effects of said disorders at a younger age, therefore when the child reaches adulthood they are better managed with any condition they may have. 

1. Conclusion

         Based on the data shown/ collected the idea that motor control, motivation, reward, cognitive function, maternal and reproductive behaviors are influenced by the dopaminergic system. The dopaminergic system has direct effects on psychological function through many genders, ages, and ethnicities. The dopaminergic system is also correlated with many chronic neurological illnesses, and direct implications with Parkinson’s, ADHD, Hungtingtons etc. 

      The most dopaminergic area of the brain is the prefrontal cortex. The TH-immunohistological approach labeled significantly more boutons than the DAT-transgenic approach in the prefrontal cortex. These preliminary results indicate the Th antibody is more comprehensive in quantifying dopamine boutons than a transgenic DAT reporter. Knowing this, future research should be obtained by utilizing the strongest labeling method, the TH-immunohistological approach.   

      Overall, Numerous physiological processes, such as mood, motor control, motivation, reward, cognitive function, maternal and reproductive behaviors depend on dopamine. Dopamine signaling at the structural level can be evaluated by looking at dopaminergic axon boutons, which are the places where dopamine is released. When there is an imbalance or lack there of dopamine A person cannot perform at their best. Despite the significant amount of research already done regarding this chemical, the research is very significant and needs to continue in order to keep making connections and developing new findings on the cause and effects a person’s dopamine level can have. As well as what disorders are linked to chemical imbalances of dopamine. 

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References

Bailey, R. K., & Owens, D. L. (2005, October). Overcoming challenges in the diagnosis and treatment of attention-deficit/hyperactivity disorder in African Americans. Journal of the National Medical Association. Retrieved November 28, 2022, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2640622/ 

What is the role of dopamine in childhood neurological disorders? (n.d.). Retrieved November 28, 2022, from https://onlinelibrary.wiley.com/doi/pdf/10.1111/dmcn.12130 

Yao, W.-D., Spealman, R. D., & Zhang, J. (2008, June 1). Dopaminergic signaling in dendritic spines. Retrieved November 28, 2022, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2443745/

Juárez Olguín H, Calderón Guzmán D, Hernández García E, Barragán Mejía G. The Role of Dopamine and Its Dysfunction as a Consequence of Oxidative Stress. Oxid Med Cell Longev. 2016;2016:9730467. doi: 10.1155/2016/9730467. Epub 2015 Dec 6. PMID: 26770661; PMCID: PMC4684895.

The relationship between childhood trauma, dopamine release and dexamphetamine-induced positive psychotic symptoms: a [11C]-(+)-PHNO PET study. (2019, January 17). Translational Psychiatry. Retrieved November 28, 2022, from https://www.nature.com/articles/s41398-019-0627-y#Sec2